HIV transmission via breastfeeding accounts for nearly half of the 350,000 infant HIV infections occurring annually. While HIV is readily transmitted from mother-to-child via breastfeeding, it has been recognized both observationally and experimentally that SIV is not or is only rarely transmitted through breastfeeding to infants of natural hosts of SIV. This lack of SIV transmission via breastfeeding is not attributable to low virus RNA load in the breast milk compartment, as maternal milk virus load in nonpathogenic SIV infection is similar to that of HIV and pathogenic SIV infection. Therefore, the infants of natural hosts of SIV are highly exposed, uninfected population, warranting evaluation of the factors contributing to the impediment of virus transmission in this setting. Elucidation of mechanisms that evolved to protect breastfeeding infants of natural hosts of SIV from postnatal SIV infection will inform immunologic strategies to reduce HIV transmission via breastfeeding. Importantly, we identified robust autologous virus neutralizing antibody response in milk of AGMs. In contrast, an autologous virus neutralization response is not detectable in milk of SIV-infected RMs or HIV-infected women. This effective virus-specific mucosal antibody response in milk of AGMs may impede virus transmission in the infant oral/gastrointestinal tract. Our previous work isolating HIV Envelope-specific monoclonal antibodies from colostrum B cells of HIV-infected women has identified novel HIV Env-specific neutralizing mucosal antibodies produced in the setting of chronic HIV infection. Therefore, identification of SIV Env-specific memory B cell responses in breast milk of nontransmitting natural hosts of SIV will define novel virus-specific mucosal antibody functions that may effectively block of mucosal virus transmission to a highly exposed, uninfected infant population, in contrast to the B cell responses of pathogenic SIV and HIV infection. This proposal is being submitted in response to the NIAID Program Announcement PA-11-217 Mechanistic Studies of HIV-exposed Seronegative Individuals, specifically addressing the topic of mucosal parameters that are distinctly different in the resistant population (SIV-infected AGM mother- infant pairs) compared to the nonresistant population (SIV-infected RMs and HIV-infected humans mother-infant pairs). PUBLIC HEALTH RELEVANCE: HIV transmission via breastfeeding accounts for nearly half of the 350,000 infant HIV infections occurring annually. Impeding postnatal HIV transmission, while maintaining the nutritional and immune benefits of breastfeeding, is critical to improving HIV-free survival of infants in regions of high HIV prevalence. Mechanisms that protect infants from postnatal virus acquisition have evolved in natural hosts of SIV, a phenomenon that is not attributable to limited virus exposure. Moreover, a potent neutralizing antibody response was detected in breast milk of natural hosts of SIV, a response that is absent in postnatal-transmitting monkey species and HIV-infected humans. Therefore, defining the immunologic mechanisms contributing to protection of infants of natural hosts of SIV from virus acquisition will guide the development of interventions to prevent HIV transmission via breastfeeding.